Malaria control interventions, including insecticide-impregnated bed nets, insecticide spraying, and antimalarial drugs, have reduced malaria morbidity and mortality substantially (World Health Organization, World Malaria Report: 2013 (2013; www.who/int/malaria/publications/world_malaria_report_2013/report/en/). However, in 2010, despite these measures, there were an estimated 220 million clinical cases and 0.66 to 1.24 million deaths caused by malaria (World Health Organization, World Malaria Report: 2012, C. J. Murray et al., Lancet 379, 413-431 (2012)). A highly effective vaccine will be ideal for preventing malaria in individuals and eliminating malaria in defined geographic areas. It would optimally target the parasite at asymptomatic, pre-erythrocytic stages (C. V. Plowe et al., J. Infect. Dis. 200, 1646-1649 (2009), malERA Consultative Group on Vaccines, A research agenda for malaria eradication: vaccines. PLoS Med. 8, e1000398 (2011)). The World Health Organization malaria vaccine technology roadmap set a vaccine efficacy goal of 80% by 2025 (Malaria Vaccine Technology Roadmap, 2006; www.malariavaccine.org/files/Malaria_Vaccine_TRM_Final.pdf).
On the other hand, it has been known for over 40 years that high-level, enduring protective immunity can be provided by means of the bites of >1000 mosquitoes, infected with radiation attenuated Plasmodium falciparum (Pf) sporozoites (SPZ) (R. S. Nussenzweig, et al., Nature 216, 160-162 (1967); D. F. Clyde, et al., Am. J. Med. Sci. 266, 169-177 (1973); K. H. Rieckmann, et al., Trans. R. Soc. Trop. Med. Hyg. 68, 258-259 (1974); S. L. Hoffman, et al., J. Infect. Dis. 185, 1155-1164 (2002)). However, mosquito bite is not a useful way to administer sporozoites and as a practical matter, a whole sporozoite vaccine approach would require the capacity to manufacture live, aseptic, radiation-attenuated, purified, preserved PfSPZ as the immunogen of an injectable vaccine that meets regulatory standards (T. C. Luke, et al., J. Exp. Biol. 206, 3803-3808 (2003); S. L. Hoffman, et al., Hum. Vac. 6, 97-106 (2010); J. E. Epstein, et al., Science 334, 475-480 (2011)).
The first clinical trial of PfSPZ Vaccine, comprising the Pf NF54 strain of SPZ (T. Ponnudurai, et al., Trans. R. Soc. Trop. Med. Hyg. 76, 242-250 (1982)) was conducted in 80 immunologically naïve adults (J. E. Epstein, et al. (2011)). They received up to 6 doses of 1.35×105 SPZ subcutaneously (SC) or intradermally (ID). PfSPZ Vaccine proved safe and well-tolerated, but elicited low-level immune response and minimal protection. It was hypothesized that the limited efficacy was due to the inefficiency of the ID and SC routes of administration (J. E. Epstein, et al. (2011)). Parallel and subsequent studies in non-human primates (NHP) with the PfSPZ Vaccine showed that IV, but not SC, administration elicited potent and durable PfSPZ-specific T-cell responses in peripheral blood, and most notably in the liver (J. E. Epstein, et al. (2011)), the likely site of immune protection (S. L. Hoffman, et al., Nat. Med. 6, 1218-1219 (2000)).
Based on these results, a phase 1 clinical trial was conducted to determine safety, immunogenicity and protective efficacy of IV administration of PfSPZ Vaccine (R. A. Seder, R. A. et al., Science, 341:1359-1365 (2013)—incorporated herein by reference in its entirety). PfSPZ Vaccine-induced protection against Pf malaria was safe, well tolerated and highly protective when administered up to 6 times IV to 40 adults. Six of six adult subjects receiving 6.75×105 SPZ in 5 doses were protected as were 6 of 9 adult subjects who received 5.4×105 SPZ in 4 doses (R. A. Seder, et al. (2013)). Additional clinical trials have now been conducted and are discussed herein.
Malaria vaccine development requires an accurate measure of efficacy. The early signs, symptoms and pathology of malaria are identifiable and, if identified early, malaria can be treated. Controlled human malaria infection (CHMI) of immunized subjects is used to assess protection. While effective, CHMI is cumbersome and expensive, requiring participation of several clinicians, experts, and hospital facilities. An assay that is easy to administer and provides high sensitivity (identification of protected individuals) and specificity (identification of unprotected individuals) would therefore be very useful.